The vaginal cavity, including the vagina and cervix, provides a unique site for delivery of therapeutic agents, both for systemic and local action.
There are multiple anatomical structures which comprise the internal and external female genital tract including the clitoris, labia minora and corpus spongiosum (vestibular) erectile tissue, vagina, peri-urethral glans, urethra, Halban's fascia, anterior fornix erogenous zone, pubococcygeus muscle and cervix.
The vagina consists of a tube of autonomically-innervated smooth muscle (longitudinal outer, inner circular layer) lined by stratified squamous epithelium and a sub-dermal layer rich in capillaries. The vaginal wall consists of an inner glandular mucous type stratified squamous cell epithelium supported by a thick lamina propia. This epithelium undergoes hormone-related cyclical changes including slight keratinization of the superficial cells during the menstrual cycle. Deep in the epithelium lies the smooth muscles of the muscularis. There is a deeper surrounding fibrous layer above the muscularis which provides structural support to the vagina and is rich is collagen and elastin to allow for expansion of the. Three sets of skeletal muscles surround the vagina including the ischiocavernosum, bulbocavernosus, transverse perinei and levator ani and pubococcygeus muscles.
Women are vulnerable to diseases of the genital tract as the lining of the vagina is a permeable mucous membrane. Intercourse, lack of lubrication during intercourse, changes in the cervix during the menstrual cycle, and asymptomatic infections facilitate the transmission of infection to women. Prepubertal girls and adolescents are particularly vulnerable because their vaginal and cervical tissues may be less mature and are more readily penetrated by organisms (e.g., chlamydia and gonococcus). Postmenopausal women are more likely than younger women to get small abrasions in the vagina during sexual activity as a result of thinning of the tissue and dryness. Women who already have an infection (particularly one that causes genital lesions) are more likely to acquire or transmit another STD, including HIV. Other biological risks include the use of vaginal douches, which increase the risk of pelvic inflammatory disease (PID), and the influence of hormonal contraceptives on acquiring or transmitting an STD (e.g., increased risk of chlamydial infection with use of oral contraceptives).
In particular, the cervix is prone to several diseases, such as cervicitis (an inflammation of the uterine cervix, usually caused by infection), cancer, inflammation, erosion, intraepithelial neoplasia (CIN), polyps, dysplasia, human papillomavirus (HPV) infections causing some tumors, condylomas or warts and abnormal pregnancy.
Several factors must be taken into consideration when developing therapeutic delivery systems for the female genital system. These factors include the vaginal anatomy, the mucosal surface, the presence and composition of vaginal fluids and secretions, cervical fluids (mucus), cyclic changes and endogenous microflora. Drug stability to enzyme activity, which is quite high in vaginal environment, and is again a function of menstrual cycle and lifecycle, should also be taken into account. Topical drug delivery through the cervix, as needed to treat disorders of the cervix and uterus also presents a challenge.
Vaginal topical formulation should be compatible with daily activities, be easy to administer and provide accurate dosing. Several types of formulations are known for delivery to the vaginal cavity. While semi-solid formulations, such as creams, lotions, gels and ointments are commonly used, they are often reported to be messy, require frequent application and can be difficult to remove after use. Furthermore, application of topical gels and creams require several steps of operation. Solid formulations such as tablets, suppositories and pessaries also require frequent application, show a poor retention in vagina, and exhibit insufficient spreadability.
Rectal drug administration can be directed to both local and systemic drug delivery. It has been effectively used to treat local diseases of the anorectal area as well as an alternative to oral administration in the systemic administration of drugs. Solid suppositories are the most common dosage form used for rectal drug administration and represent the majority of rectal dosage forms; however, creams ointments and foams are also being used.
Current formulations for rectal administration still have significant disadvantages. They are difficult to insert through the anal orifice; they are difficult to spread throughout the target cavity; and if spreadable, they tend to leak, causing major discomfort to the patient. Such negative attributes lead to their very limited use.
Thus, new forms are desirable in order to achieve better control and ease of application, while maintaining the beneficial properties of such products. A product for intravaginal and anorectal application would ideally exhibit the following properties: (1) easy insertion, thus leading to high patient compliance; (2) accurate dosing, to ensure effective treatment; (3) expandability, for increased coverage of the target cavity surface and cervix; and (4) drip free formulation with good adhesive properties, for prolonged drug residence. The duration of the drug inside the vagina or rectum is also important for ensuring extended activity.
Use of emulsions in foam compositions is known. Emulsion systems provide a two-phase system including water in one phase and oily components in the second phase. Emulsifiers for reducing surface tension and for improving foam stability are included in the foam composition. Foams and, in particular, foam emulsions are complicated systems which do not form under all circumstances. Slight shifts in foam emulsion composition, such as by the addition of active ingredients, may destabilize the foam. In the case of oil-containing foams, high surfactant concentrations are required to attain foams of low density and acceptable texture.
Typical vaginal foam products are aqueous formulations and do not include significant levels of an oil-based solvent. For example. a nonoxynol-9-containing foam marketed under the trademane Delfen® foam (Advanced care, 12.5% nonoxynol-9), Emko® foam (Schering-Plough Healthcare, 12% nonoxynol-9) does not contain any oily solvent and has an ingredient list reciting “nonoxynol-9 12.5%, benzoic acid, cetyl alcohol, glacial acetic acid, methylparaben, perfume, phosphoric acid, polyvinyl alcohol, propellant a-31, propylene glycol, purified water, sodium carboxymethylcellulose, sorbic acid, stearamidoethyl diethylamine, stearic acid”.
PCT Publication No. WO 03/053292 discloses drug delivery compositions, which are suitable for vaginal administration for the treatment of diseases and disorders in the urogenital tract. The compositions may be in the form of a tablet, liquid suspension or dispersion; dried powder; topical ointment; cream; foam; suppository; or aerosol. The drug delivery compositions are administered directly to the vagina and do not require the use of a pressurized canister or other foaming device. The reference does not disclose use of hydrophobic or oily solvents.
U.S. Pat. No. 5,759,520 discloses an aqueous foamable composition having a delayed foaming action on expulsion from a pressurized container. The composition includes (a) a major amount by weight of water; (b) 0.5 to 7.0 weight percent of a foaming agent in the form of a water-immiscible liquefied gas; (c) at least one foam-stabilizing and emulsifying surfactant; and (d) a water-soluble polymer. A foaming agent such as propellant gas forms a foam upon discharge from the container. Water is used as the foam vehicle and hydrophobic organic carriers such as oil or emollients are not disclosed.
PCT Publication No. WO 02/00820 discloses a propellant-free foamable aqueous composition for use as vaginal or hemorrhoidal wipe. The aqueous stable foam includes water, at least one surfactant and at least one foam-stabilizing agent. Such compounds are storage stable and readily dispensed by a propellantless mechanical pump.
U.S. Pat. No. 5,679,324 pertains to an aerosol foamable fragrance composition, translucent in its pre-dispensed state, which forms a fast-breaking foam. The composition contains a surfactant selected from the group consisting of ethoxylated lanolin oil derivatives, propoxylated lanolin oil derivatives, and mixtures thereof, a propellant, a fragrance, a thickener, and a cosmetic vehicle (preferably water) wherein the ratio of the surfactant to propellant is from about 1:1 to about 1:10. Emollients may be included, however, being translucent, the composition cannot comprise significant oil concentrations (which would make it opaque). Apparently the foam breaks spontaneously upon discharging from an aerosol container (with no need of any rubbing or sheer force application), thus making it impractical for intravaginal application.
Additionally, U.S. Pat. Nos. 5,536,743 and 5,840,744 relate to a non-flowing composition and method for intravaginal treatment of bacterial vaginosis. The composition contains metronidazole with a buffer system providing an acidic buffered pH value in the range of 3.75 to about 4.25. Certain of the compositions disclosed are based on mineral oil or petrolatum. The foam compositions disclosed include up to 3% mineral oil as the hydrophobic component of the emulsion.
U.S. Pat. No. 6,544,530 provides a stable oil-in-glycerin composition comprising a continuous glycerin phase, at least one vegetable oil, at least one biodegradable emulsifier and at least one bioactive essential oil component for topical, external use on skin and mucosal. The essential oil is a volatile mixture of esters, aldehydes, alcohols, ketones, and terpenes that possess bioactivity such as topical anti-fungal activity, topical anti-bacterial activity, topical anti-parasitic activity, and topical anti-viral activity.
U.S. Pat. No. 5,993,846 discloses a method for making an oil-in-water emulsion having mucoadhesive properties which includes forming a mixture of a mucoadhesive macromolecule and an aqueous phase; emulsifying the mixture with a hydrophobic phase and a surfactant to form an oil-in-water emulsion comprising a plurality of submicron particles having a hydrophobic core surrounded by the surfactant and the mucoadhesive macromolecule; and providing the emulsion with a final pH of between 3 and 8.
U.S. Pat. No. 6,423,323 describes an aqueous foam emulsion. The composition includes a hydrophobic phase including fatty acids, emulsifiers and co-emulsifiers, and an aqueous phase containing hydrophilic moisturizers and emulsifiers. An optional ingredient is one or more refatting substances.
U.S. Pat. No. 6,730,288 teaches a pharmaceutical foam composition including (a) an active ingredient; (b) an occlusive agent; (c) an aqueous solvent; and (d) an organic cosolvent; wherein the active ingredient is insoluble in water and insoluble in both water and the occlusive agent; and wherein there is enough occlusive agent to form an occlusive layer on the skin.